Coronary heart disease (CHD) is the leading cause of death in the United States, affecting 1 million people each year. The term "cardiovascular vulnerable patient" has been used to describe patients susceptible to acute coronary events based upon plaque, blood, or myocardial characteristics. Recent evidence also has suggested that depression is a significant and independent risk factor for patients with CHD, and also may be associated with increased cardiovascular vulnerability. This evidence has provided a rationale for developing interventional strategies for treating depression in cardiac patients. Antidepressant medications, especially selective serotonin reuptake inhibitors, have been particularly effective in this regard. However, for many patients medication fails to adequately relieve depressive symptoms or does so at the cost of unwanted side effects. Thus, there is a need to identify alternative approaches for treating depression, particularly in patients with CHD. There is now good reason to believe that exercise may be one such approach. To date, however, the therapeutic potential of exercise has remained unfulfilled due to a paucity of data from well-designed clinical studies of depressed patients, and virtually no randomized controlled trials of depressed CHD patients. The study proposed in this application will build upon our previous work in which we demonstrated the feasibility and efficacy of exercise as a treatment for depression. Specifically, we propose to (a) evaluate the effectiveness of exercise training in reducing depression in vulnerable cardiac patients; (b) examine changes in intermediate endpoints, including measures of autonomic nervous system dysregulation, endothelial dysfunction, chronic inflammation, and platelet activation, which also serve as physiologic markers of cardiac vulnerability to arrhythmias, plaque rupture, and thrombosis; and (c) explore possible mechanisms by which the interventions reduce depression. Two hundred men and women with CHD and elevated symptoms of depression will be randomly assigned to Exercise, Medication, or Placebo. Before and after 3 months of treatment, patients will undergo clinical assessments of depression and measures of heart rate variability, baroreflex control, endothelial function, C-reactive protein, and platelet activity. A six month follow-up will assess maintenance of benefit and evaluate cardiac events and medical cost utilization. The data generated from this study will have important clinical significance by determining the extent to which exercise may reduce depression and improve intermediate markers of CHD risk in vulnerable cardiac patients. [unreadable] [unreadable]